Dermoscopic similarity is an independent predictor of BRAF mutational concordance in multiple melanomas.

BACKGROUND: The association of clinical and dermoscopic features with BRAF mutational status has been poorly analysed in multiple primary melanomas (MPM). OBJECTIVE: To investigate whether concordance of BRAF mutational status is associated with dermoscopic similarity in multiple melanomas of the same patient. METHODS: Dermoscopic images and corresponding tissue sections of 124 melanomas from 62 patients with MPM were selected at four Italian Dermatology Departments. Similarity of dermoscopic appearance between multiple melanomas was evaluated according to the presence of the same prevalent dermoscopic feature. The BRAFV600 mutational status was analysed with allele-specific TaqManTM assays or pyrosequencing. Spearman's correlation and univariate and multivariate regression analysis were used for statistical analysis. RESULTS: A similar dermoscopic appearance was identified in 38.7% (24/62) of patients with MPM and was correlated with older age at first diagnosis (rho: 0.26; P: 0.042) and occurrence on sun-damaged skin (rho: 0.27; P: 0.037). The BRAFV600 mutation was detected in 39.5% (49/124) of the tumors and a concordant BRAF mutational status between melanomas in 33/62 (53.2%) MPM patients. Dermoscopically similar melanomas showed 5.7-fold higher odds to be concordant for BRAF mutational status compared to dissimilar lesions (OR: 5.7; 95% CI 1.7-19.5; P: 0.005). CONCLUSION: Dermoscopic similarity of multiple melanomas represents an independent clinical predictor of a concordant BRAF mutational status in MPM patients.

Interferon-beta injection site reactions in patients with multiple sclerosis.

Interferon-beta (IFNß) is effective treatments for relapsing multiple sclerosis (MS). IFNß treatment includes subcutaneous (SC) IFNß-1b, intramuscular (IM) and SC IFNß-1a, and SC pegylated IFNß-1a (PEG-IFNß-1a). PEG-IFNß-1a offers the advantage of a prolonged duration of action with a less frequent administration (every 2 weeks) and a higher patient adherence. However, the use of SC interferons could be characterized by potential skin toxicity. Injection site reactions (ISRs), featured by erythema, edema, pain, and pruritus, are the most common adverse reactions. ISRs are mild or moderate in the vast majority of cases, but they can be severe enough to induce drug discontinuation. Therefore, it is very important to adopt strategies to minimize ISRs by proper patient education and counseling. These include rotation of injection sites, use of autoinjectors, use of medication at room temperature, cold compress, or local anesthetic cream before injection, early application of medium to high potency topical corticosteroids with gauze medication, and nonsteroidal anti-inflammatory drugs taken before and for 24 h after the injection.

A new dermoscopic algorithm for the differential diagnosis of facial lentigo maligna and pigmented actinic keratosis.

The clinical and dermoscopic diagnosis of facial lentigo maligna (LM) and pigmented actinic keratosis (PAK) remains challenging, particularly at the early disease stages. To identify dermoscopic criteria that might be useful to differentiate LM from PAK, and to elaborate and validate an automated diagnostic algorithm for facial LM/PAK. We performed a retrospective multicentre study to evaluate dermoscopic images of histologically-proven LM and PAK, and assess previously described dermoscopic criteria. In the first part of the study, 61 cases of LM and 74 PAK were examined and a parsimonious algorithm was elaborated using stepwise discriminant analysis. The following eight dermoscopic criteria achieved the greatest discriminative power: (1) light brown colour; (2) a structureless zone, varying in colour from brown to brown/tan, to black; (3) in-focus, discontinuous brown lines; (4) incomplete brown or grey circles; (5) a structureless brown or black zone, obscuring the hair follicles; (6) a brown (tan), eccentric, structureless zone; (7) a blue structureless zone; and (8) scales. The newly developed algorithm was subsequently validated using an additional series of 110 LM and 75 PAK cases. Diagnostic accuracy was 86.5% (κ: 0.73, 95% CI: 0.63-0.83). For the diagnosis of LM vs PAK, sensitivity was 82.7% (95% CI: 75.7-89.8%), specificity was 92.0% (95% CI: 85.9-98.1%), positive predictive value was 93.8% (95% CI: 89.0-98.6%), and negative predictive value was 78.4% (95% CI: 68.4-86.5%). This algorithm may represent an additional tool for clinicians to distinguish between facial LM and PAK.

Heterogeneity of BRAF, NRAS, and TERT Promoter Mutational Status in Multiple Melanomas and Association with MC1R Genotype: Findings from Molecular and Immunohistochemical Analysis.

Data on somatic heterogeneity and germline-somatic interaction in multiple primary melanoma (MPM) patients are limited. We investigated the mutational status of BRAF, NRAS, and TERT promoter genes in 97 melanomas of 44 MPM patients and compared molecular and immunohistochemical findings. We further evaluated the association of somatic alterations with the germline MC1R genotype. Mutations in BRAF gene were identified in 41.2% (40/97) of melanomas, in NRAS in 2.1% (2/97), and in TERT promoter in 19.6% (19/97). Distribution of BRAF mutations did not differ across multiple melanomas (P = 0.85), whereas TERT promoter changes decreased from first to subsequent melanomas (P = 0.04). Intrapatient discrepancy of BRAF mutations among multiple tumors was detected in 14 of 44 MPM patients (32%) and of BRAF/NRAS/TERT promoter genes in 20 of 44 (45%). We observed a high rate of agreement between allele-specific TaqMan assay and immunohistochemistry in BRAFV600E detection (κ = 0.83, P < 0.01) with 86 of 97 melanomas (88.7%) presenting similar BRAF status. Germline MC1R variants were identified in 81.4% (35/43) of MPM patients with no association of MC1R genotype with somatic mutations or with intrapatient concordance of somatic mutational profile. Our results support the genetic diversity of multiple melanomas and show that somatic heterogeneity is not influenced by inherited MC1R variants. Immunohistochemistry may be useful as an initial screening test.

Staging and follow-up of cutaneous melanoma patients.

Melanoma is responsible for the greatest number of deaths caused by skin malignancies. The purpose of monitoring patients diagnosed with melanoma is to allow early detection of recurrence and any subsequent primary tumors. Several dermatological and oncological societies developed their own set of guidelines for the surveillance and management of melanoma patients depending on the stage of the disease. The object of this article is to provide a comprehensive, systematic overview that summarizes and interprets previous studies, to characterize current practices regarding progression of melanoma, division into stages of development, and subsequent surveillance. We have performed a systematic review search to December 2016 using the MEDLINE database and performed a manual search of selected references. We examined the staging system and the different surveillance programs for melanoma patients. Consistent recommendations with proven evidence are available for staging melanoma patients. Conversely, recommendations are more controversial for follow-up procedures. Given the inadequate number of randomized controlled trials, consensus on the best, universally-applicable follow-up procedure has not been reached and interpretation of the roles of imaging and laboratory tests, as well as of the appropriate frequency and duration of physical examinations, vary widely. Based on a universally-accepted staging system different surveillance procedures have been developed, which may be mainly classified in two groups: low- and high-intensity strategies.

Characterization of melanoma susceptibility genes in high-risk patients from Central Italy.

Genetic susceptibility to cutaneous melanoma has been investigated in Italian high-risk melanoma patients from different geographical regions. CDKN2A, CDK4, and MC1R genes have been screened in most studies, MITF and POT1 were screened in only one study, and none analyzed the TERT promoter. We carried out a mutational analysis of CDKN2A, CDK4 exon 2, POT1 p.S270N, MITF exon 10, MC1R, and the TERT promoter in 106 high-risk patients with familial melanoma (FM) and sporadic multiple primary melanoma (spMPM) from Central Italy and evaluated mutations according to the clinicopathological characteristics of patients and lesions. In FM, CDKN2A mutations were detected in 8.3% of the families, including one undescribed exon 1ß mutation (p.T31M), and their prevalence increased with the number of affected relatives within the family. MC1R variants were identified in 65% of the patients and the TERT rs2853669 promoter polymorphism was identified in 58% of the patients. A novel synonymous mutation detected in MITF exon 10 (c.861A>G, p.E287E), although predicted as a splice site mutation by computational tools, could not functionally be confirmed to alter splicing. For spMPM, 3% carried CDKN2A mutations, 79% carried MC1R variants, and 47% carried the TERT rs2853669 promoter polymorphism. MC1R variants were associated with fair skin type and light hair color both in FM and in spMPM, and with a reduction of age at diagnosis in FM patients. Mutations in CDK4 exon 2 and the POT1 p.S270N mutation were not detected. A low frequency of CDKN2A mutations and a high prevalence of MC1R variants characterize high-risk melanoma patients from Central Italy.